Abstract

Helminths facilitate their own survival by actively modulating the immune systems of their hosts. We investigated the impacts that different life cycle stages of the rodent filaria Litomosoides sigmodontis have on the inflammatory responses of mice injected with sublethal doses of lipopolysaccharide (LPS). Mice infected with female adult worms from prepatent infections, worms which have not yet started to release microfilariae, developed lower levels of proinflammatory cytokines in the peripheral blood after LPS challenge than sham-treated controls, demonstrating that female adult worms can mitigate the innate immune response. The presence of microfilariae in mice, however, through either direct injection or implantation of microfilaria-releasing adult female worms, turned the LPS challenge fatal. This lethal outcome was characterized by increased plasma levels of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), and IL-6, greater numbers of macrophages and granulocytes in the peripheral blood, and decreased body temperatures in microfilaria-infected mice. Microfilaria-infected mice deficient in IFN-gamma receptor and TNF receptor 1 had increased survival rates after LPS challenge compared to immune-competent mice, suggesting that microfilariae worsen LPS-induced sepsis through actions of IFN-gamma and TNF-alpha. In summary, we have demonstrated that infection of mice with L. sigmodontis female adult worms from prepatent infections protects mice injected with LPS whereas microfilariae worsen LPS-induced sepsis through the induction of proinflammatory cytokines and upregulation of granulocytes, NK cells, and monocytes in the peripheral blood.

Cytokine production [log (pg/ml + 0.5)] of infected or sham-treated C57BL/6 mice 6 hours (IFN-γ, IL-6, IL-12, and IL-10) and 1 hour (TNF-α) after LPS challenge. Mice were infected with female adult worms from prepatent (n = 4), patent (n = 8 to 10), and postpatent (n = 3) infections or male worms (n = 4), while the controls (n = 22) got the same surgical treatment but no worms. The data with worms from patent infections and control mice were obtained from two independent experiments. Significant differences between infected mice and the control group were analyzed by the Kruskal-Wallis test, followed by Dunn's post hoc multiple comparisons (*, P < 0.05).

Cell populations in the peripheral blood samples of C57BL/6 mice (n = 7 per group) treated with microfilariae (Mf) and LPS or microfilariae and PBS as well as the corresponding sham-treated controls (“Control” in LPS and PBS groups). Significant differences were determined by the Wilcoxon/Kruskal-Wallis test after stabilization of data by arcsinus transformation [arcsin (square root of values in percentage/100)]. Significant differences between the PBS-injected control group and the other groups are displayed with a single star, and horizontal bars with stars indicate any additional significant differences (*, P < 0.05).